Dopamine D2 receptor function is compromised in the brain of the methionine sulfoxide reductase A knockout mouse

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Wiley

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Article

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Scholarly/refereed, author accepted manuscript

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This is the peer reviewed version of the following article: Oien, D. B., Ortiz, A. N., Rittel, A. G., Dobrowsky, R. T., Johnson, M. A., Levant, B., Fowler, S. C. and Moskovitz, J. (2010), Dopamine D2 receptor function is compromised in the brain of the methionine sulfoxide reductase A knockout mouse. Journal of Neurochemistry, 114: 51–61. , which has been published in final form at http://doi.org/10.1111/j.1471-4159.2010.06721.x. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.

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Abstract

Previous research suggests that brain oxidative stress and altered rodent locomotor behavior are linked. We observed bio-behavioral changes in methionine sulfoxide reductase A knockout mice associated with abnormal dopamine signaling. Compromised ability of these knockout mice to reduce methionine sulfoxide enhances accumulation of sulfoxides in proteins. We examined the dopamine D2-receptor function and expression, which has an atypical arrangement and quantity of methionine residues. Indeed, protein expression levels of dopamine D2-receptor were higher in knockout mice compared with wild-type. However, the binding of dopamine D2-receptor agonist was compromised in the same fractions of knockout mice. Coupling efficiency of dopamine D2-receptors to G-proteins was also significantly reduced in knockout mice, supporting the compromised agonist binding. Furthermore, pre-synaptic dopamine release in knockout striatal sections was less responsive than control sections to dopamine D2-receptor ligands. Behaviorally, the locomotor activity of knockout mice was less responsive to the inhibitory effect of quinpirole than wild-type mice. Involvement of specific methionine residue oxidation in the dopamine D2-receptor third intracellular loop is suggested by in vitro studies. We conclude that ablation of methionine sulfoxide reductase can affect dopamine signaling through altering dopamine D2-receptor physiology and may be related to symptoms associated with neurological disorders and diseases.